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Journal of Genetics Dec 2015X-chromosome inactivation, which was discovered by Mary Lyon in 1961 results in random silencing of one X chromosome in female mammals. This review is dedicated to Mary... (Review)
Review
X-chromosome inactivation, which was discovered by Mary Lyon in 1961 results in random silencing of one X chromosome in female mammals. This review is dedicated to Mary Lyon, who passed away last year. She predicted many of the features of X inactivation, for e.g., the existence of an X inactivation center, the role of L1 elements in spreading of silencing and the existence of genes that escape X inactivation. Starting from her published work here we summarize advances in the field.
Topics: Animals; Gene Silencing; Humans; X Chromosome; X Chromosome Inactivation
PubMed: 26690513
DOI: 10.1007/s12041-015-0574-1 -
Cells Feb 2022Early in development, placental and marsupial mammals harbouring at least two X chromosomes per nucleus are faced with a choice that affects the rest of their lives:... (Review)
Review
Early in development, placental and marsupial mammals harbouring at least two X chromosomes per nucleus are faced with a choice that affects the rest of their lives: which of those X chromosomes to transcriptionally inactivate. This choice underlies phenotypical diversity in the composition of tissues and organs and in their response to the environment, and can determine whether an individual will be healthy or affected by an X-linked disease. Here, we review our current understanding of the process of choice during X-chromosome inactivation and its implications, focusing on the strategies evolved by different mammalian lineages and on the known and unknown molecular mechanisms and players involved.
Topics: Animals; Dosage Compensation, Genetic; Female; Mammals; Marsupialia; Placenta; Pregnancy; X Chromosome; X Chromosome Inactivation
PubMed: 35159344
DOI: 10.3390/cells11030535 -
Cell Feb 2024Autoimmune diseases disproportionately affect females more than males. The XX sex chromosome complement is strongly associated with susceptibility to autoimmunity. Xist...
Autoimmune diseases disproportionately affect females more than males. The XX sex chromosome complement is strongly associated with susceptibility to autoimmunity. Xist long non-coding RNA (lncRNA) is expressed only in females to randomly inactivate one of the two X chromosomes to achieve gene dosage compensation. Here, we show that the Xist ribonucleoprotein (RNP) complex comprising numerous autoantigenic components is an important driver of sex-biased autoimmunity. Inducible transgenic expression of a non-silencing form of Xist in male mice introduced Xist RNP complexes and sufficed to produce autoantibodies. Male SJL/J mice expressing transgenic Xist developed more severe multi-organ pathology in a pristane-induced lupus model than wild-type males. Xist expression in males reprogrammed T and B cell populations and chromatin states to more resemble wild-type females. Human patients with autoimmune diseases displayed significant autoantibodies to multiple components of XIST RNP. Thus, a sex-specific lncRNA scaffolds ubiquitous RNP components to drive sex-biased immunity.
Topics: Animals; Female; Humans; Male; Mice; Autoantibodies; Autoimmune Diseases; Autoimmunity; Ribonucleoproteins; RNA, Long Noncoding; X Chromosome; X Chromosome Inactivation; Sex Characteristics
PubMed: 38306984
DOI: 10.1016/j.cell.2023.12.037 -
Development (Cambridge, England) Mar 2021The peri-implantation window of mammalian development is the crucial window for primordial germ cell (PGC) specification. Whereas pre-implantation dynamics are... (Review)
Review
The peri-implantation window of mammalian development is the crucial window for primordial germ cell (PGC) specification. Whereas pre-implantation dynamics are relatively conserved between species, the implantation window marks a stage of developmental divergence between key model organisms, and thus potential variance in the cell and molecular mechanisms for PGC specification. In humans, PGC specification is very difficult to study To address this, the combined use of human and nonhuman primate embryos, and stem cell-based embryo models are essential for determining the origin of PGCs, as are comparative analyses to the equivalent stages of mouse development. Understanding the origin of PGCs in the peri-implantation embryo is crucial not only for accurate modeling of this essential process using stem cells, but also in determining the role of global epigenetic reprogramming upon which sex-specific differentiation into gametes relies.
Topics: Animals; Cell Differentiation; DNA Methylation; Embryonic Development; Embryonic Stem Cells; Germ Cells; Humans; Models, Biological; X Chromosome
PubMed: 33722957
DOI: 10.1242/dev.189217 -
Cell Dec 2021The lncRNA Xist forms ∼50 diffraction-limited foci to transcriptionally silence one X chromosome. How this small number of RNA foci and interacting proteins regulate a...
The lncRNA Xist forms ∼50 diffraction-limited foci to transcriptionally silence one X chromosome. How this small number of RNA foci and interacting proteins regulate a much larger number of X-linked genes is unknown. We show that Xist foci are locally confined, contain ∼2 RNA molecules, and nucleate supramolecular complexes (SMACs) that include many copies of the critical silencing protein SPEN. Aggregation and exchange of SMAC proteins generate local protein gradients that regulate broad, proximal chromatin regions. Partitioning of numerous SPEN molecules into SMACs is mediated by their intrinsically disordered regions and essential for transcriptional repression. Polycomb deposition via SMACs induces chromatin compaction and the increase in SMACs density around genes, which propagates silencing across the X chromosome. Our findings introduce a mechanism for functional nuclear compartmentalization whereby crowding of transcriptional and architectural regulators enables the silencing of many target genes by few RNA molecules.
Topics: Animals; Apoptosis Regulatory Proteins; Cell Line; Embryonic Stem Cells; Fibroblasts; Gene Silencing; Humans; Mice; Mitochondrial Proteins; Protein Binding; RNA, Long Noncoding; X Chromosome; X Chromosome Inactivation
PubMed: 34813726
DOI: 10.1016/j.cell.2021.10.022 -
Cell Jan 2024X chromosome inactivation (XCI) serves as a paradigm for RNA-mediated regulation of gene expression, wherein the long non-coding RNA XIST spreads across the X chromosome...
X chromosome inactivation (XCI) serves as a paradigm for RNA-mediated regulation of gene expression, wherein the long non-coding RNA XIST spreads across the X chromosome in cis to mediate gene silencing chromosome-wide. In female naive human pluripotent stem cells (hPSCs), XIST is in a dispersed configuration, and XCI does not occur, raising questions about XIST's function. We found that XIST spreads across the X chromosome and induces dampening of X-linked gene expression in naive hPSCs. Surprisingly, XIST also targets specific autosomal regions, where it induces repressive chromatin changes and gene expression dampening. Thereby, XIST equalizes X-linked gene dosage between male and female cells while inducing differences in autosomes. The dispersed Xist configuration and autosomal localization also occur transiently during XCI initiation in mouse PSCs. Together, our study identifies XIST as the regulator of X chromosome dampening, uncovers an evolutionarily conserved trans-acting role of XIST/Xist, and reveals a correlation between XIST/Xist dispersal and autosomal targeting.
Topics: Animals; Female; Humans; Male; Mice; Gene Silencing; Genes, X-Linked; RNA, Long Noncoding; X Chromosome; Pluripotent Stem Cells
PubMed: 38181737
DOI: 10.1016/j.cell.2023.11.033 -
Cold Spring Harbor Perspectives in... May 2022In female eutherian mammals, dosage compensation of X-linked gene expression is achieved during development through transcriptional silencing of one of the two X... (Review)
Review
In female eutherian mammals, dosage compensation of X-linked gene expression is achieved during development through transcriptional silencing of one of the two X chromosomes. Following X chromosome inactivation (XCI), the inactive X chromosome remains faithfully silenced throughout somatic cell divisions. XCI is dependent on , a long noncoding RNA that coats and silences the X chromosome from which it is transcribed. coating triggers a cascade of chromosome-wide changes occurring at the levels of transcription, chromatin composition, chromosome structure, and spatial organization within the nucleus. XCI has emerged as a paradigm for the study of such crucial nuclear processes and the dissection of their functional interplay. In the past decade, the advent of tools to characterize and perturb these processes have provided an unprecedented understanding into their roles during XCI. The mechanisms orchestrating the initiation of XCI as well as its maintenance are thus being unraveled, although many questions still remain. Here, we introduce key aspects of the XCI process and review the recent discoveries about its molecular basis.
Topics: Animals; Cell Nucleus; Dosage Compensation, Genetic; Female; Mammals; RNA, Long Noncoding; X Chromosome; X Chromosome Inactivation
PubMed: 34312245
DOI: 10.1101/cshperspect.a040196 -
Genetics Feb 2022Abnormalities in chromosome number have the potential to disrupt the balance of gene expression and thereby decrease organismal fitness and viability. Such abnormalities... (Review)
Review
Abnormalities in chromosome number have the potential to disrupt the balance of gene expression and thereby decrease organismal fitness and viability. Such abnormalities occur in most solid tumors and also cause severe developmental defects and spontaneous abortions. In contrast to the imbalances in chromosome dose that cause pathologies, the difference in X-chromosome dose used to determine sexual fate across diverse species is well tolerated. Dosage compensation mechanisms have evolved in such species to balance X-chromosome gene expression between the sexes, allowing them to tolerate the difference in X-chromosome dose. This review analyzes the chromosome counting mechanism that tallies X-chromosome number to determine sex (XO male and XX hermaphrodite) in the nematode Caenorhabditis elegans and the associated dosage compensation mechanism that balances X-chromosome gene expression between the sexes. Dissecting the molecular mechanisms underlying X-chromosome counting has revealed how small quantitative differences in intracellular signals can be translated into dramatically different fates. Dissecting the process of X-chromosome dosage compensation has revealed the interplay between chromatin modification and chromosome structure in regulating gene expression over vast chromosomal territories.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Disorders of Sex Development; Dosage Compensation, Genetic; Female; Genes, X-Linked; Male; X Chromosome
PubMed: 35100381
DOI: 10.1093/genetics/iyab197 -
Philosophical Transactions of the Royal... Nov 2017X-chromosome inactivation (XCI) is a critical epigenetic mechanism for balancing gene dosage between XY males and XX females in eutherian mammals. A long non-coding RNA... (Review)
Review
X-chromosome inactivation (XCI) is a critical epigenetic mechanism for balancing gene dosage between XY males and XX females in eutherian mammals. A long non-coding RNA (lncRNA), XIST, and its associated proteins orchestrate this multi-step process, resulting in the inheritable silencing of one of the two X-chromosomes in females. The XIST RNA is large and complex, exemplifying the unique challenges associated with the structural and functional analysis of lncRNAs. Recent technological advances in the analysis of macromolecular structure and interactions have enabled us to systematically dissect the XIST ribonucleoprotein complex, which is larger than the ribosome, and its place of action, the inactive X-chromosome. These studies shed light on key mechanisms of XCI, such as XIST coating of the X-chromosome, recruitment of DNA, RNA and histone modification enzymes, and compaction and compartmentalization of the inactive X. Here, we summarize recent studies on XCI, highlight the critical contributions of new technologies and propose a unifying model for XIST function in XCI where modular domains serve as the structural and functional units in both lncRNA-protein complexes and DNA-protein complexes in chromatin.This article is part of the themed issue 'X-chromosome inactivation: a tribute to Mary Lyon'.
Topics: Animals; Chromatin; Chromosomes, Human, X; Female; Humans; Mice; Models, Genetic; RNA, Long Noncoding; X Chromosome; X Chromosome Inactivation
PubMed: 28947655
DOI: 10.1098/rstb.2016.0356 -
Proceedings of the National Academy of... Jan 2023Reactivation of the inactive X chromosome is a hallmark epigenetic event during reprogramming of mouse female somatic cells to induced pluripotent stem cells (iPSCs)....
Reactivation of the inactive X chromosome is a hallmark epigenetic event during reprogramming of mouse female somatic cells to induced pluripotent stem cells (iPSCs). This involves global structural remodeling from a condensed, heterochromatic into an open, euchromatic state, thereby changing a transcriptionally inactive into an active chromosome. Despite recent advances, very little is currently known about the molecular players mediating this process and how this relates to iPSC-reprogramming in general. To gain more insight, here we perform a RNAi-based knockdown screen during iPSC-reprogramming of mouse fibroblasts. We discover factors important for X chromosome reactivation (XCR) and iPSC-reprogramming. Among those, we identify the cohesin complex member SMC1a as a key molecule with a specific function in XCR, as its knockdown greatly affects XCR without interfering with iPSC-reprogramming. Using super-resolution microscopy, we find SMC1a to be preferentially enriched on the active compared with the inactive X chromosome and that SMC1a is critical for the decompacted state of the active X. Specifically, depletion of SMC1a leads to contraction of the active X both in differentiated and in pluripotent cells, where it normally is in its most open state. In summary, we reveal cohesin as a key factor for remodeling of the X chromosome from an inactive to an active structure and that this is a critical step for XCR during iPSC-reprogramming.
Topics: Female; Animals; Mice; Induced Pluripotent Stem Cells; Cellular Reprogramming; X Chromosome Inactivation; X Chromosome; Chromosome Structures; Cohesins
PubMed: 36669113
DOI: 10.1073/pnas.2213810120